DESCRIPTION (Applicant's Description) Colon carcinogenesis is a multi-stage process in which adenoma formation, growth and malignant transformation occur sequentially. There is substantial evidence for adenomatous polyps being precursors of colorectal adenocarcinomas. Environmental factors in combination with genetic susceptibility are thought to play a major role in the etiology of both colorectal adenomas and cancer. The proposed study focuses on a recently identified, frequently occurring genetic polymorphism resulting in a thermolabile form of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Individuals with homo- or heterozygous genotype for MTHFR have reduced enzyme activities (30% and 65% of the mean normal activity, respectively). Reduced MTHFR activity may cause DNA hypomethylation, an abnormality which has been observed in the earlier stages of colon cancer development. The thermolabile MTHFR genotype is highly prevalent: approximately 12% of the Caucasian population are homozygotes and about 50% are heterozygotes with respect to the mutation; thus, this polymorphism is potentially of considerable public health importance. The aim of the proposed study is to evaluate whether the thermolabile MTHFR polymorphism is associated with an increased risk of adenomatous colorectal polyps, and whether this risk is especially increased in individuals who consume a diet low in folate or low in other dietary methyl group sources or high in alcohol (factors plausibly related to DNA hypomethylation). We will test these hypotheses within an existing case-control study of adenomatous colorectal polyps in which blood samples and extensive dietary information on the participants have been collected. We propose to determine the thermolabile MTHFR genotypes of 500 cases with adenomatous polyps and 500 colonoscopy-negative controls using a PCR-RFLP method. Logistic regression analyses will be used to estimate the risk of adenomatous polyps associated with the thermolabile MTHFR genotype, both overall and within subgroups. The proposed study represents a cost-effective approach to examine potential gene-environment interactions in the development of colorectal neoplasia.